Arthritis is the most common chronic musculoskeletal disorder, affecting nearly 23 million patients or 9% of the U.S. population, with osteoarthritis (OA) comprising about 70% of that patient population. Arthritis is the leading age-related medical condition among women and ranks as the second most common such condition among men over 45 years of age. Deformities or orthopaedic joint impairment rank sixth among chronic disorders causing activity limitations.
As an age-related condition, the continued projected growth of the elderly as a percentage of the total population will increase the prevalence of arthritis. Increasing longevity of the elderly population will further accelerate the incidence of age-related conditions such as arthritis. A significant portion of elderly arthritis sufferers are afflicted seriously enough to be considered disabled. Through the year 2000, the disabled elderly population is expected to increase to over 7 million (18% of elderly) patients, and more than double to 15-20 million over the subsequent fifty years.
Hospitalizations resulting from arthritis are the second highest admissions category (8-10% of patients), followed by other orthopaedic impairments as the fourth leading category. Each year, approximately 1.3 million patients are admitted to U.S. hospitals for arthritis treatment, 85% of which are osteoarthritis patients.
Of the half million arthroplasty procedures performed annually in the U.S., approximately 80% are performed on the hip and knee. Osteoarthritis is estimated to account for 50% of hip arthroplasties and over 80% of knee arthroplasties. Hip and knee osteoarthritis are the two most common forms of joint cartilage degeneration. Both forms of osteoarthritis occur most commonly in patients over 50 years old. Hip osteoarthritis is characterized by movement pain, joint stiffness and eventually deformity of the hip.
Osteoarthritis can be a primary degenerative process, result from childhood hip disorders, or as secondary to adult injury, infection, endocrine/metabolic disorders or bone dysplasia. Depending on the patient""s age, their range of hip motion and clinical presentation, current operative procedures range from arthrodesis in young patients and osteotomy in patients under 60 years with reasonable hip motion, to hemi-, total, resection and cup arthroplasty. Knee osteoarthritis is characterized by pain, joint swelling, stiffness, motion loss and eventually deformity. As with the hip, knee osteoarthritis may be a primary degenerative process or result from a single or repeated knee injuries.
Osteoarthritis is a progressively degenerative disease, resulting in increasing pain, impairment and ultimately disability. While the available treatments seek to ameliorate pain or improve mobility, these treatments rarely modify the course of the disease, but rather attend to its consequences. For early stage osteoarthritis, treatment is largely limited to addressing the symptoms of inflammation with non-steroidal anti-inflammatory drugs, steroids for acute exacerbation and some use of the more toxic Disease-Modifying Arthorheumatic Drugs (DMARDS, e.g. gold salts, penicillamine, and methotrexate). Clinical reports indicate that even the newest DMARDS, such as tenidap, will not materially improve the clinical outcomes. None of these treatments stop the progression of the condition nor regenerate damaged cartilage.
Depending on the patient""s age and health status, current operative treatment involves proximal tibial or distal femoral osteotomy, unicompartmental knee replacement, or total knee arthroplasty. Evolving treatment procedures include arthroscopic debridement, abrasion/drilling of chondral defects and articular cartilage allografts.
No approaches currently exist to adequately treat arthritic patients, despite the large number of patients who could benefit from treatments which are less invasive than end-stage joint replacement. Once the condition has progressed to substantial articular cartilage damage, none of the currently available approaches are adequate.
Various groups have initiated cell seeding-absorbable matrix projects using mature differentiated chondrocytes. One such group is developing a cell-seeded absorbable matrix for non-weight bearing cartilage, while another is using a purified bovine collagen matrix for meniscal repair.
The approach of yet another group is a chondrocyte-seeded collagen matrix for articular cartilage repair. Others are investigating a yearly, and very costly multi-injection regimen of hydroxyapatite into the synovium to decrease pain and to delay arthroplasty in osteoarthritis patients.
Various reports of progress in cartilage repair demonstrate that partial repair of shallow joint cartilage injury may be feasible in younger patients. Using a technique which incorporates culture expanded mature cartilage cells (chondrocytes), these procedures provide encouraging initial results as to the potential role for cell therapy in cartilage repair. Despite these various attempts, cartilage repair is not yet possible.
As observed in arriving at the present invention, clinical acceptance will require more sophisticated cell therapy approaches designed to recapitulate the complete sequence of tissue-forming eventsxe2x80x94that is, starting with tissue progenitor cells (human mesenchymal stem cells or hMSCs) which form cartilage, bone, muscle, bone marrow stroma, ligament, tendon and connective tissue prenatally, and applying the same technology to the regeneration of injured and diseased tissue in adults.
Human mesenchymal stem cell technology provides not only multiple opportunities to regenerate cartilage, but other mesenchymal tissue as well, including bone, muscle, tendon, marrow stroma and dermis. The regeneration of cartilage and other injured or diseased tissue is achieved by administration of an optimal number of human mesenchymal stem cells to the repair site in an appropriate biomatrix delivery device, without the need for a second surgical site to harvest normal tissue grafts. Furthermore, opportunities also exist to use human mesenchymal stem cell technology for gene therapy, cancer treatment, bone marrow transplantation, and for the treatment of osteoporosis and osteoarthritis.
For repair of cartilage damaged as part of the degenerative effects of osteoarthritis, the present inventors have found that the human mesenchymal stem cell approach makes it possible to: (1) regenerate both shallow cartilage chondral defects and full thickness cartilage defects (osteochondral lesions); (2) broaden the suitable clinical population to routinely include middle-aged patients; (3) eliminate the use of autologous tissue grafts (mature cartilage and the periosteal covering) to repair an articular cartilage injury; (4) regenerate other types of injured cartilage such as patellar and spinal disk cartilage; (5) regenerate articular joint cartilage in older patients with osteoarthritis; and (6) form new cartilage and subchondral bone which fully integrate into the adjacent normal tissue.
The process of developing the present invention focused on the use of autologous mesenchymal stem cells for the regeneration of stable hyaline cartilage in affected joints. The articular cartilage of the knee and hip joints was the target of initial focus because the greatest morbidity and debilitating conditions in osteoarthritis arise from degeneration or degradation of these joints in the leg.
The most promising approach to articular cartilage repair appears to be the use of autologous mesenchymal stem cells, which are osteochondral precursors. Mesenchymal stem cells for articular cartilage repair are combined with a controlled-resorption biodegradable matrix, preferably collagen-based products. These mesenchymal stem cell-matrix implants initiate, de novo, tissue formation, and maintain and stabilize the articular defect during the repair process. In addition to gels, the types of biomatrix materials that may be used include sponges, foams or porous fabrics that form a three-dimensional scaffold for the support of mesenchymal stem cells. These materials may be composed of collagen, gelatin, hyaluronan or derivatives thereof, or may consist of synthetic polymers, or may consist of composites of several different materials. The different matrix configurations and collagen formulations will depend on the nature of the cartilage defect, and include those for both open surgical and arthroscopic procedures.
Several formulations of autologous, culture-expanded mesenchymal stem cells that serve as the basis of therapies for osteoarthritis are contemplated, depending on the stage, joint location, and severity of the disease. They are (1) a gel formulation that can be applied to osteochondral defects during arthroscopy; (2) an injectable cell suspension for delivery directly to the synovial space; and (3) a molded mesenchymal stem cell-biomatrix product to re-surface joint surfaces in advanced cases.
The methods, compositions and implant devices of the invention are particularly suited for established conditions where superficial chondral or osteochondral defects can be diagnosed, but prior to the point where there is widespread joint instability and bone destruction. A characteristic indicator of chondral defect is a visibly altered gait or use of the joint to accommodate the discomfort or stiffness resulting from tissue damage, and the objective of treatment is to regenerate full thickness articular cartilage at the site of the defects to thereby prevent the joint destabilization and rapid joint destruction which are common sequelae of advanced osteoarthritis.
Patients ranging in age from 30-50 years with one or more well-defined articular cartilage lesions (as determined by imaging modalities or diagnostic arthroscopy) are ideal candidates for treatment in accordance with the invention. The need for advanced surgical intervention involving osteotomy or total joint arthroplasty can be deferred or even obviated.
Administration is by application of culture-expanded (preferably autologous) human mesenchymal stem cells in a biodegradable collagen and/or fibrin matrix implant and/or blood serum clots to the affected joint. Application typically involves an arthroscopic procedure, which may include debridement of the defect prior to implantation of the human mesenchymal stem cell matrix. Within six to twelve weeks following implantation, the graft develops into fill thickness cartilage with complete bonding to the subchondral bone.
Approximately a month prior to the initial treatment of the patient, a bone marrow aspirate (e.g., approximately 10-20 ml) is obtained from the patient""s medial posterior iliac crest using standard aseptic techniques in an out-patient procedure. A Bone Marrow Collection and Transport Kit, described herein, provides most or all of the material needed for safe and efficient collection, identification, and transportation of the collected bone marrow. The double-sealed collection vessel is refrigerated until ready for human mesenchymal stem cell processing. A single aspirate sample can be culture-expanded sufficiently to provide material for multiple lesions (4-6) during one or several arthroscopic procedures. The cryopreservation techniques described herein permit retention of that portion of the aspirate that is not needed currently until it is required.
In a preferred embodiment, the implant is a two-component product consisting of a culture-expanded human mesenchymal stem cell suspension or cryopreserved human mesenchymal stem cells in one sterile transport device and a flowable collagen matrix in another sterile transport device. The contents of the two transport devices are admixed in a combined or third separate sterile implant chamber (closed system) which attaches by means of custom couplers (supplied with the procedure tray) to fit standard arthroscopes. The implant chamber provides the means to freshly mix human mesenchymal stem cells with biomatrix at the time of the operative procedure. The implant chamber is maintained for a sufficient gelation time for the cell-matrix to achieve the proper viscosity, and allows the orthopaedist or the rheumatologist to adjust the procedure and/or implant volume to conform to the actual lesion configuration.